New hope for a drug that could impact all cancer types
The telomeres are disposable buffers blocking the ends of the chromosomes and are consumed during cell division and replenished by an enzyme, the telomerase reverse transcriptase. In 1985 it was shown that the enzyme telomerase elongates telomeres, which shorten during every cell division. (For more information on telomeres please refer to the post: Telomeres resemble DNA fragile sites.)
Transcription factor: In the field of molecular biology, a transcription factor (sometimes called a sequence-specific DNA binding factor) is a protein that binds to specific DNA sequences and thereby controls the transfer (or transcription) of genetic information from DNA to RNA. Transcription factors perform this function alone or with other proteins in a complex, by promoting (as an activator), or blocking (as a repressor) the recruitment of RNA polymerase (the enzyme which performs the transcription of genetic information from DNA to RNA) to specific genes. A defining feature of transcription factors is that they contain one or more DNA binding domains (DBDs) which attach to specific sequences of DNA adjacent to the genes that they regulate. (Refer to post: Scientists use the zebrafish to gain insight into the development of melanoma.)
Myc (cMyc) gene encodes for a transcription factor that is believed to regulate expression of 15% of all genes through binding to the DNA of these genes. When a gene like Myc is altered to cause cancer, the cancerous version of the gene is called an oncogene. The healthy version of the gene that it is derived from is called a proto-oncogene. A mutated version of Myc is found in many cancers which causes Myc to be persistently expressed. This leads to the unregulated expression of many genes some of which are involved in cell proliferation and results in the formation of cancer.
Ras is a family of genes that are involved in cellular signal transduction. Activation of Ras signalling causes cell growth, differentiation and survival. Since Ras communicates signals from outside the cell to the nucleus, mutations in ras genes can permanently activate it and cause inappropriate transmission inside the cell even in the absence of extracellular signals. Because these signals result in cell growth and division, dysregulated Ras signaling can ultimately lead to oncogenesis and cancer. Activating mutations in Ras are found in 20-25% of all human tumors and up to 90% in specific tumor types.
TP53 and Retinoblastoma protein (pRb) are tumor suppressor proteins.
PP2A: PP2A gene encodes the phosphatase 2A catalytic subunit. Protein phosphatase 2A is one of the four major Serine/threonine phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. This gene encodes an alpha isoform of the catalytic subunit.
Role of telomerase in actual human tumors
For the formation of tumorigenic cells in a variety of cell types the following alterations are required: activation of Telomerase Reverse Transcriptase (TERT), loss of TP53 pathway function, loss of pRb pathway function, activation of the Ras or myc proto-oncogenes, and aberration of the PP2A protein phosphatase. This means the cell has an activated telomerase, eliminating the process of death by chromosome instability or loss, absence of apoptosis-induction pathways, and continued activation of mitosis. This model of cancer in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase activation has been observed in ~90% of all human tumors, suggesting that the immortality conferred by telomerase plays a key role in cancer development.
Key interaction that controls telomeres – Work done by researchers at University of Michigan Comprehensive Cancer Center.
Researchers at the University of Michigan Comprehensive Cancer Center have traced a mechanism that stops cells from becoming cancerous.
Telomerase is kept in control by the protein TRF1, which keeps the telomeres operating correctly. But another protein, Fbx4, can bind to TRF1 and degrade it, causing the telomeres to lengthen. Now, researchers at the University of Michigan Comprehensive Cancer Center have discovered, a third protein, TIN2, that steps in and overrides Fbx4 by binding to TRF1 first and preventing Fbx4 from attaching to it.
The researchers found that the location in the molecule where Fbx4 binds to TRF1 overlaps with where TIN2 binds to TRF1. Where both Fbx4 and TIN2 are present, the TIN2 wins out and binds to the TRF1 first. This blocks Fbx4 from binding to the TRF1, thereby stabilizing TRF1 and keeping the telomere length in control.
One of the researchers, Dr. Ming Lei, assistant professor of biological chemistry, says, “In 90 percent of cancers, no matter what caused the cancer to form, it needs telomerase activity to maintain the cell. Without telomerase, the cell will die. Our work is key to understanding a detailed mechanism for how these molecules interact and how to design a drug to block Fbx4.”
The researchers are now looking at peptides that mimic TIN2’s binding to TRF1, in order to block Fbx4.
Based on this discovery if a drug is discovered it could impact all cancer types. Dr. Lei says, “If we find a drug that can inhibit telomerase activity in any fashion, that could be a universal cancer drug.”
The research team also included Zhixiong Zeng, Wei Wang, Yuting Yang, Yong Chen, Xiaomei Yang, J. Alan Diehl, and Xuedong Liu.
Source: http://www2.med.umich.edu/prmc/media/newsroom/details.cfm?ID=1489
February 17, 2010